Plasmacytoma-like post-transplantation lymphoproliferative disorder confined to the renal allograft: a case report.

A 44-year-old woman who had end-stage kidney disease from diabetes and hypertension underwent a deceased donor kidney transplantation. Eighteen months after the transplantation she developed an abrupt increase in her creatinine level and a kidney biopsy specimen showed the presence of a plasma cell-rich infiltrate. A vast majority of the plasma cells were kappa (κ) light chain restricted on in situ hybridization. κ and lambda (λ) free light chain were elevated in her serum and so was the κ/λ ratio. A bone marrow biopsy specimen showed no evidence of clonal plasmacytosis. A positron emission tomography (PET) scan showed hypermetabolic activity confined to the kidney. Prior to transplantation she was Epstein-Barr virus (EBV) immunoglobulin (Ig)G-negative but had detectable EBV based on polymerase chain reaction (PCR) in her blood during this episode. Despite reduction in immunosuppression there was no change in the κ/λ ratio and her renal function worsened. She underwent a transplant nephrectomy and her κ/λ ratio became normal. Twenty-one months later she is lymphoma-free and doing well on dialysis. Plasmacytoma-like post-transplantation lymphoproliferative disorder (PTLD) is rare and even more is the localization of the malignancy to the allograft. When reduction of immunosuppression is unsuccessful in treatment, removal of the organ may be necessary as is demonstrated in our case.

Kidney-limited thrombotic microangiopathy in patients with SLE treated with romiplostim.

We present the case of a 19 year-old Caucasian female with history of systemic lupus erythematosus (SLE) and normal baseline kidney function who developed severe acute renal failure following treatment of thrombocytopenia with the thrombopoietic agent romiplostim. Percutaneous kidney biopsy revealed thrombotic microangiopathy (TMA) without immune complex lupus glomerulonephritis. We discuss pathogenesis and differential diagnosis of TMA in patients with SLE and raise concerns regarding the use of thrombopoietic agents in such patients. Based on favorable long-term outcome in our case aggressive treatment and in particular prolonged use of plasma exchange in these patients are advocated.

Designing an adaptive phase II/III trial to evaluate efficacy, safety and immune correlates of new TB vaccines in young adults and adolescents.

This article summarises the consensus arrived at a meeting of South African and international stakeholders on specific late phase clinical trial design issues integrating the investigation of immune correlates as an integral part of a phase III protocol for a preventative TB vaccine in an adolescent/adult population. The challenge ahead is to optimize the planning for phase 3 TB vaccine preventative trials, under resource constraints, given that there are no known correlates of protection to shorten and increase the efficiencies of efficacy trials. An adaptive, multi-arm, group sequentially designed trial protocol is proposed incorporating design features that address uncertainties arising from both advances in the field and dynamic study populations and disease states. Such a design allows modifications that protect research subjects, save time, and maximize the impact of scarce financial resources. Further, the protocol underwent joint review by regulators from several African nations at a meeting of the African Vaccine Regulatory Forum (AVAREF), a regional regulatory harmonization initiative, and recommendations are included.

Acute antibody-mediated rejection following heart transplantation.

Acute antibody-mediated rejection (AMR) in heart transplantation is often associated with hemodynamic compromise, and is associated with increased mortality and development of accelerated transplant coronary artery disease (TCAD). The diagnosis of AMR has historically been controversial and outcomes with aggressive immunosuppressive therapy including plasmapheresis and cyclophosphamide are poor. Advances in diagnostic techniques like the demonstration of immunopathologic evidence for antibody-mediated rejection by deposition of the complement split product C4d in tissue and detection of anti-HLA antibodies by flow cytometry will assist in further characterizing AMR. Immunosuppression targeting B-lymphocytes and use of m-TOR inhibitors to alter the predilection to develop TCAD and improve survival in AMR remains to be proven.

Joint inferences on vaccine efficacy against infection and disease with application to the first HIV vaccine efficacy trial.

In many clinical trials, subjects are followed for two stages of outcomes, and it is of interest to compare the incidence of each outcome between two randomized groups. The outcome of the first stage may influence the outcome of the second stage. Moreover, the relative risks of the two outcomes may be linked, with the time-dependent profile of relative risk for the second outcome functionally dependent on that of the first. For example, during exposure to HIV, virologic and host factors simultaneously impact the probability of infection and the subsequent viral trajectories, and the efficacy of a tested vaccine to prevent infection and to prevent viral failure may work in concert. We address this problem by modeling the relationship between the stage two hazard function and covariates via Cox's proportional hazards model (Cox, 1972), with the stage one log-hazard ratio theta(*) at the first event time Tl, included as a covariate. With theta(*) estimated using three methods, 1) nonparametric kernel smoothing; 2) locally parametric penalized splines; and 3) fully parametric cubic linear splines, we subsequently develop inference procedures for the regression parameter in the stage two Cox model based on each of the estimator of theta(*). The inferential procedures are studied in simulations and are illustrated with application to data from the world's first preventive HIV vaccine efficacy trial.

The effects and consequences of very large explosive volcanic eruptions.

Every now and again Earth experiences tremendous explosive volcanic eruptions, considerably bigger than the largest witnessed in historic times. Those yielding more than 450km3 of magma have been called super-eruptions. The record of such eruptions is incomplete; the most recent known example occurred 26000 years ago. It is more likely that the Earth will next experience a super-eruption than an impact from a large meteorite greater than 1km in diameter. Depending on where the volcano is located, the effects will be felt globally or at least by a whole hemisphere. Large areas will be devastated by pyroclastic flow deposits, and the more widely dispersed ash falls will be laid down over continent-sized areas. The most widespread effects will be derived from volcanic gases, sulphur gases being particularly important. This gas is converted into sulphuric acid aerosols in the stratosphere and layers of aerosol can cover the global atmosphere within a few weeks to months. These remain for several years and affect atmospheric circulation causing surface temperature to fall in many regions. Effects include temporary reductions in light levels and severe and unseasonable weather (including cool summers and colder-than-normal winters). Some aspects of the understanding and prediction of super-eruptions are problematic because they are well outside modern experience. Our global society is now very different to that affected by past, modest-sized volcanic activity and is highly vulnerable to catastrophic damage of infrastructure by natural disasters. Major disruption of services that society depends upon can be expected for periods of months to, perhaps, years after the next very large explosive eruption and the cost to global financial markets will be high and sustained.

Introduction: Is viral shedding a surrogate marker for transmission of genital herpes?

Genital herpes, caused by either herpes simplex virus type 1 or 2 (HSV-1 and HSV-2), is a significant public health problem worldwide. It increases the risk of infection with HIV, upregulates HIV after infection and can be associated with serious morbidity and mortality. It is now known that clinical and subclinical viral reactivation with resultant shedding from anogenital mucosa occurs frequently, resulting in transmission during sexual contact. Sexual transmission of HSV infection is common, even between monogamous individuals. Antiviral therapy reduces the frequency and degree of viral shedding and lowers the transmission rate in discordant monogamous couples, although transmission can still occur in people prescribed antiviral therapy. These encouraging data raise important questions for the management of genital HSV infection, particularly with regard to the prevention of transmission. Although the quantity of virus present is clearly important in transmission of some viruses, it is not clear whether this is the case for HSV transmission. Ideally, a surrogate marker needs to be able to identify individuals with detectable amounts of virus, and differentiate them from individuals with detectable amounts of virus that are transmissible. The aim of this supplement is to explore the issues surrounding the validation of surrogate markers of transmission of HSV, using examples from other human viral diseases, and to review the available evidence. In the future, exploration of these issues may shed light on management and prevention strategies. In particular, the results may clarify what evidence is required to warrant prescribing a drug for reducing HSV transmission, and for which patient populations this strategy is appropriate.

Lessons from HIV and hepatitis viruses.

Surrogate markers are an important component in the process of investigating management and prevention strategies, and for increasing understanding of viral diseases. The importance of surrogate markers and applied statistical models is particularly true for HIV. For HIV infection, the development of such methods provides new approaches for evaluation of HIV therapies and vaccines, and for the study of HIV transmission and its pathogenesis. The complex natural history of hepatitis B infection demonstrates that viral load is not the only predictor of transmission of this virus; for hepatitis C infection, viral load per se is not a prognostic factor for disease progression, but cumulative viral load may affect the outcome, and therapy is aimed at eliminating active viral replication.

HSV shedding.

Viral shedding of HSV occurs frequently in infected individuals. HSV is shed asymptomatically from multiple anatomical sites and shedding, like exposure, is a significant risk for transmission. However, the relationship between shedding frequency, viral titer and transmission is unknown. HSV-2 shedding is affected by the site and time since acquisition of infection. The advent of sensitive PCR techniques has shown that the magnitude and frequency of viral shedding is higher than shown previously with viral culture techniques. It has also clearly demonstrated that suppressive (daily) antiviral therapy reduces clinical and subclinical reactivation rates, and has been successfully used in the prevention of recurrent oral and genital HSV infections. A recent study has demonstrated that daily antiviral therapy with valaciclovir can significantly reduce transmission of HSV-2 between discordant heterosexual couples in monogamous relationships.

HSV-2 transmission.

A number of important risk factors for the acquisition of HSV-2 have been established including female gender, black or Hispanic ethnic origin, HIV infection, age, and increased number of sexual partners. Transmission is influenced by a number of biological factors such as sexual behavior, use of condoms, duration of relationships, and knowledge of a partner's serologic status. Vertical transmission (transmission of HSV from mother to neonate) is potentially life-threatening; neonatal HSV infection is associated with significant morbidity and mortality. The valaciclovir transmission study provides evidence that an antiviral agent can interrupt the transmission of a viral sexually transmitted disease between serologically discordant sexual partners. This review explores the importance of the cofactors that affect transmission, and makes recommendations on considerations for the prophylactic use of antiviral agents for the prevention of transmission in other patient populations.

A regression modeling approach for describing patterns of HIV genetic variation.

We introduce a novel approach for describing patterns of HIV genetic variation using regression modeling techniques. Parameters are defined for describing genetic variation within and between viral populations by generalizing Simpson's index of diversity. Regression models are specified for these variation parameters and the generalized estimating equation framework is used for estimating both the regression parameters and their corresponding variances. Conditions are described under which the usual asymptotic approximations to the distribution of the estimators are met. This approach provides a formal statistical framework for testing hypotheses regarding the changing patterns of HIV genetic variation over time within an infected patient. The application of these methods for testing biologically relevant hypotheses concerning HIV genetic variation is demonstrated in an example using sequence data from a subset of patients from the Multicenter AIDS Cohort Study.

Safety and immunogenicity of a canarypox-vectored human immunodeficiency virus Type 1 vaccine with or without gp120: a phase 2 study in higher- and lower-risk volunteers.

Live attenuated viral vectors that express human immunodeficiency virus (HIV) antigens are being developed as potential vaccines to prevent HIV infection. The first phase 2 trial with a canarypox vector (vCP205, which expresses gp120, p55, and protease) was conducted in 435 volunteers with and without gp120 boosting, to expand the safety database and to compare the immunogenicity of the vector in volunteers who were at higher risk with that in volunteers at lower risk for HIV infection. Neutralizing antibodies to the MN strain were stimulated in 94% of volunteers given vCP205 plus gp120 and in 56% of volunteers given vCP205 alone. CD8(+) cytotoxic T lymphocyte cells developed at some time point in 33% of volunteers given vCP205, with or without gp120. Phase 3 field trials with these or similar vaccines are needed, to determine whether efficacy in preventing HIV infection or in slowing disease progression among vaccinees who become infected is associated with the level and types of immune responses that were induced by the vaccines in this study.

Are US populations appropriate for trials of human immunodeficiency virus vaccine? The HIVNET Vaccine Preparedness Study.

Questions exist about whether testing of preventive human immunodeficiency virus (HIV)-1 vaccines, which will require rapid recruitment and retention of cohorts with high HIV-1 seroincidence, is feasible in the United States. A prospective cohort study was conducted in 1995-1997 among 4,892 persons at high risk for HIV infection in nine US cities. At 18 months, with an 88% retention rate, 90 incident HIV-1 infections were observed (1.31/100 person-years (PY), 95% confidence interval (CI): 1.06, 1.61). HIV-1 seroincidence rates varied significantly by baseline eligibility criteria--1.55/100 PY among men who had sex with men, 0.38/100 PY among male intravenous drug users, 1.24/100 PY among female intravenous drug users, and 1.13/100 PY among women at heterosexual risk-and by enrollment site, from 0.48/100 PY to 2.18/100 PY. HIV-1 incidence was highest among those men who had sex with men who reported unprotected anal intercourse (2.01/100 PY, 95% CI: 1.54, 2.63), participants who were definitely willing to enroll in an HIV vaccine trial (1.96/100 PY, 95% CI: 1.41, 2.73), and women who used crack cocaine (1.62/100 PY, 95% CI: 0.92, 2.85). Therefore, cohorts with HIV-1 seroincidence rates appropriate for HIV-1 vaccine trials can be recruited, enrolled, and retained.

Treatment of primary human immunodeficiency virus type 1 infection with potent antiretroviral therapy reduces frequency of rapid progression to AIDS.

Immunologic data supporting immediate antiretroviral therapy in primary human immunodeficiency virus type 1 (HIV-1) infection are emerging; however, clinical benefit has not been demonstrated. The clinical and virologic course of 47 patients who were enrolled from September 1993 through June 1996 and who were not initially treated with potent therapy was compared with the course of 20 patients who immediately began therapy with zidovudine, lamivudine, and indinavir. Demographic and baseline laboratory data were comparable. During 78 weeks of follow-up, the early-treatment cohort showed a reduced frequency of opportunistic infections (5% vs. 21.3%; relative risk, 0.11; P=.02), less frequent progression to AIDS (13% vs. 0%), and significantly less frequent nonopportunistic mucocutaneous disorders and respiratory infections (P<.01). Plasma HIV-1 RNA levels were <50 copies/mL in all patients who continued therapy; however, after 9--12 months, HIV-1 remained detectable in latently infected CD4(+) T cells and in lymph node mononuclear cells. Combination antiretroviral therapy during primary HIV-1 infection demonstrated a decreased frequency of minor opportunistic infections, mucocutaneous disorders, and respiratory infections and reduced progression to AIDS.

Sieve analysis: methods for assessing from vaccine trial data how vaccine efficacy varies with genotypic and phenotypic pathogen variation.

A key component in the evaluation of efficacy of a vaccine to protect against disease caused by an antigenically diverse infectious pathogen in a preventative vaccine trial is assessing how vaccine-induced protection depends on genotypic and phenotypic variations of the exposing pathogen. This assessment is made by comparing pathogen isolates between infected vaccinated subjects and infected unvaccinated subjects. A survey of efficacy trial reports reveals a lack of systematic, quantitative investigation in this question. Analysis tools for testing if vaccine protection against disease is superior against some pathogen strains, and for estimating the magnitude of this differential vaccine protection, are described. The broad applicability of the methods is illustrated through analysis of isolates taken from persons infected while participating in vaccine trails for cholera, HIV-1, hepatitis B, rotavirus, and pneumococcus. These analyses reveal intriguing trends for Genentech's monovalent rgp120 HIV-1 vaccine, for two whole-killed-cell oral cholera vaccines, and for other vaccines.

Ischiospinal dysostosis with rib gaps and nephroblastomatosis.

Rib gaps, vertebral ossification defects, hypoplastic ischial bones and large kidneys were present in a newborn. A renal biopsy showed nephroblastomatosis . The observation links two recently described conditions - 'ischiospinal dysostosis' and 'a new syndrome comprising vertebral anomalies and multicystic kidneys' - and shows that nephroblastomatosis may be a manifestation of ischiospinal dysostosis. Ischiospinal dysostosis with nephroblastomatosis is one of a group of disorders characterized by developmental defects of the axial skeleton. It must be added to the conditions predisposing to Wilms tumor formation.

Continuous combined hormone replacement therapy and risk of endometrial cancer.

OBJECTIVE: Postmenopausal women who receive sequential hormone replacement therapy with estrogen combined with progestogen for 10 to 24 d/mo for a prolonged period may have an elevated endometrial cancer risk relative to those who have never received hormone replacement therapy. We investigated whether daily use of estrogen and progestogen (continuous combined hormone replacement therapy) could diminish any excess endometrial cancer risk. STUDY DESIGN: A population-based study in Washington State obtained interview data from 969 women aged 45 to 74 years with endometrial cancer diagnosed during 1985 through 1991 or 1994 through 1995 and from 1325 age-matched control subjects selected primarily by random digit dialing. Women who had received only continuous combined hormone replacement therapy were compared with women who had only received another hormone replacement therapy regimen or who had never received hormone replacement therapy. RESULTS: The risk of endometrial cancer among users of continuous combined hormone replacement therapy (n = 9 case patients, n = 33 control subjects) relative to women who had never received hormone replacement therapy was 0.6 (95% confidence interval, 0.3-1.3); the risk relative to women who received hormone replacement that included progestogen for 10 to 24 d/mo was 0.4 (95% confidence interval, 0.2-1.1). Most continuous combined hormone replacement therapy use was short-term (<72 months) or recent (in the previous 24 months). CONCLUSION: Women who had received continuous combined hormone replacement therapy for several years did not appear to be at any increased risk for endometrial cancer relative to women who had never received hormone replacement therapy and may in fact be at decreased risk for endometrial cancer.

Early HIV infection in vivo: branching-process model for studying timing of immune responses and drug therapy.

We propose a stochastic, branching-process model of early events in vivo in human or simian immunodeficiency virus (HIV or SIV) infection and study the influence that the time of appearance of virus-specific antibodies or cytotoxic cells, or of administration of antiretroviral drugs, has on the probability of progression to a chronic infection. In some biological scenarios, our model predicts that a few days' delay in response or intervention would make little difference, while in others it would be highly deleterious. We show that prophylactic efficacy does not require perfect efficiency at neutralizing infectious virus. Data from a trial of PMPA, a potent antiretroviral drug, as post-exposure therapy for SIV infection in macaques, reported by C.-C. Tsai, P. Emau, K.E. Follis, T.W. Beck, R. E. Beneveniste, N. Bischofberger, J.D. Lifson, W.R. Morton (J. Virol. 72 (1998) 4265), provides a test of the model. We show that their observations are consistent with a branching-process without invoking supplementary viral- or host-variability. Finally, most animal trials of antiviral drugs or vaccines use very high viral inoculums; our model demonstrates that in such experiments we risk greatly underestimating the efficacy of these agents.

Acute renal artery and vein thrombosis after renal transplant, associated with a short partial thromboplastin time and factor V Leiden mutation.

Renal graft thrombosis is a rare but devastating complication of renal transplantation. It accounts for one-third to one-half of early graft losses. We report a patient with acute renal artery and vein thrombosis associated with abnormally short activated partial thromboplastin time (aPTT) and factor V Leiden mutation. Vascular thrombosis developed on the ninth post-transplant day and led to a graft loss. Before transplantation, the patient had three episodes of thrombosis of arteriovenous access for hemodialysis. Our case illustrates the importance of investigating pretransplant patients for hypercoagulable states, particularly those with short aPTT.